Level Of Ganglion Research Articles

Diagnosis of Dizziness Due to a Core Vestibular Projection Injury in a Patient with Intracerebral Hemorrhage.

Herein, we present a patient diagnosed with dizziness due to a core vestibular projection injury following intracerebral hemorrhage (ICH). A 51-year-old female patient underwent conservative management for a spontaneous ICH in the left hemisphere (mainly affecting the basal ganglia and insular cortex). When she visited the rehabilitation department of the university hospital at two years after the ICH onset, she advised of the presence of moderate dizziness (mainly, light-headedness) that started after ICH onset. She mentioned that her dizziness had decreased slightly over time. No abnormality was observed in the vestibular system of either ear on physical examination by an otorhinolaryngologist. However, diffusion tensor tractography results showed that the core vestibular projection in the left hemisphere was discontinued at the basal ganglia level compared with the patient’s right core vestibular projection and that of a normal subject. Therefore, it appears that the dizziness in this patient can be ascribed to a left core vestibular projection injury.

Synaptic and cellular plasticity in Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease, which causes a tremendous socioeconomic burden. PD patients are suffering from debilitating motor and nonmotor symptoms. Cardinal motor symptoms of PD, including akinesia, bradykinesia, resting tremor, and rigidity, are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In addition, decreased amounts of dopamine (DA) level in the basal ganglia induces numerous adaptive changes at the cellular and synaptic levels in the basal ganglia circuits. These cellular and synaptic adaptations are believed to underlie the emergence and propagation of correlated, rhythmic pattern of activity throughout the interconnected cortico-basal ganglia-thalamocortical network. The widespread pathological pattern of brain activity is closely linked to the devastating motor symptoms of PD. Accumulating evidence suggests that both dopaminergic degeneration and the associated abnormal cellular and circuit activity in the basal ganglia drive the motor symptoms of PD. In this short review I summarize the recent advances in our understanding of synaptic and cellular alterations in two basal ganglia nuclei (i.e. the striatum and the subthalamic nucleus) following a complete loss of DA, and in our conceptual understanding of the cellular and circuit bases for the pathological pattern of brain activity in parkinsonian state.

Skeletal Muscle Reflex-Induced Sympathetic Dysregulation and Sensitization of Muscle Afferents in Type 1 Diabetic Rats.

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; P<0.05), mechanoreflex (21±13 versus 51±20%; P<0.05), and metaboreflex (40±20 versus 88±39%; P<0.01) activation in T1DM rats evoked significant increases in renal sympathetic nerve activity as well as mean arterial pressure. The response of group IV afferents to mechanical (18±24 versus 61±45 spikes; P<0.01) and chemical (0.3±0.4 versus 1.6±0.8 Hz; P<0.01) stimuli were significantly greater in T1DM than control. T1DM rats showed markedly increased pPKCα levels in dorsal root ganglia compared with control. These data suggest that in T1DM, abnormally muscle reflex-evoked increases in sympathetic activity mediate exaggerations in blood pressure. Further, sensitization of muscle afferents, potentially via PKC activation, may contribute to this abnormal circulatory responsiveness.

Targeting interleukin-20 alleviates paclitaxel-induced peripheral neuropathy.

The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.

Enhanced T-type calcium channel 3.2 activity in sensory neurons contributes to neuropathic-like pain of monosodium iodoacetate-induced knee osteoarthritis.

The monosodium iodoacetate knee osteoarthritis model has been widely used for the evaluation of osteoarthritis pain, but the pathogenesis of associated chronic pain is not fully understood. The T-type calcium channel 3.2 (CaV3.2) is abundantly expressed in the primary sensory neurons, in which it regulates neuronal excitability at both the somata and peripheral terminals and facilitates spontaneous neurotransmitter release at the spinal terminals. In this study, we investigated the involvement of primary sensory neuron-CaV3.2 activation in monosodium iodoacetate osteoarthritis pain. Knee joint osteoarthritis pain was induced by intra-articular injection of monosodium iodoacetate (2 mg) in rats, and sensory behavior was evaluated for 35 days. At that time, knee joint structural histology, primary sensory neuron injury, and inflammatory gliosis in lumbar dorsal root ganglia, and spinal dorsal horn were examined. Primary sensory neuron-T-type calcium channel current by patch-clamp recording and CaV3.2 expression by immunohistochemistry and immunoblots were determined. In a subset of animals, pain relief by CaV3.2 inhibition after delivery of CaV3.2 inhibitor TTA-P2 into sciatic nerve was investigated. Knee injection of monosodium iodoacetate resulted in osteoarthritis histopathology, weight-bearing asymmetry, sensory hypersensitivity of the ipsilateral hindpaw, and inflammatory gliosis in the ipsilateral dorsal root ganglia, sciatic nerve, and spinal dorsal horn. Neuronal injury marker ATF-3 was extensively upregulated in primary sensory neurons, suggesting that neuronal damage was beyond merely knee-innervating primary sensory neurons. T-type current in dissociated primary sensory neurons from lumbar dorsal root ganglia of monosodium iodoacetate rats was significantly increased, and CaV3.2 protein levels in the dorsal root ganglia and spinal dorsal horn ipsilateral to monosodium iodoacetate by immunoblots were significantly increased, compared to controls. Perineural application of TTA-P2 into the ipsilateral sciatic nerve alleviated mechanical hypersensitivity and weight-bearing asymmetry in monosodium iodoacetate osteoarthritis rats. Overall, our findings demonstrate an elevated CaV3.2 expression and enhanced function of primary sensory neuron-T channels in the monosodium iodoacetate osteoarthritis pain. Further study is needed to delineate the importance of dysfunctional primary sensory neuron-CaV3.2 in osteoarthritis pain.

Pain modulation effect on motor cortex after optogenetic stimulation in shPKCγ knockdown dorsal root ganglion-compressed Sprague-Dawley rat model.

Neuropathic pain can be generated by chronic compression of dorsal root ganglion (CCD). Stimulation of primary motor cortex can disrupt the nociceptive sensory signal at dorsal root ganglion level and reduce pain behaviors. But the mechanism behind it is still implicit. Protein kinase C gamma is known as an essential enzyme for the development of neuropathic pain, and specific inhibitor of protein kinase C gamma can disrupt the sensory signal and reduce pain behaviors. Optogenetic stimulation has been emerged as a new and promising conducive method for refractory neuropathic pain. The aim of this study was to provide evidence whether optical stimulation of primary motor cortex can modulate chronic neuropathic pain in CCD rat model. Animals were randomly divided into CCD group, sham group, and control group. Dorsal root ganglion-compressed neuropathic pain model was established in animals, and knocking down of protein kinase C gamma was also accomplished. Pain behavioral scores were significantly improved in the short hairpin Protein Kinase C gamma knockdown CCD animals during optic stimulation. Ventral posterolateral thalamic firing inhibition was also observed during light stimulation on motor cortex in CCD animal. We assessed alteration of pain behaviors in pre-light off, stimulation-light on, and post-light off state. In vivo extracellular recording of the ventral posterolateral thalamus, viral expression in the primary motor cortex, and protein kinase C gamma expression in dorsal root ganglion were investigated. So, optical cortico-thalamic inhibition by motor cortex stimulation can improve neuropathic pain behaviors in CCD animal, and knocking down of protein kinase C gamma plays a conducive role in the process. This study provides feasibility for in vivo optogenetic stimulation on primary motor cortex of dorsal root ganglion-initiated neuropathic pain.

C-type natriuretic peptide suppresses ventricular arrhythmias in rats with acute myocardial ischemia

This study aimed to investigate the effects of C-type natriuretic peptide (CNP) on ventricular arrhythmias in rats with acute myocardial ischemia (AMI). Forty male Sprague-Dawley rats were randomly divided into sham group (n = 10), AMI group (n = 15) and AMI + CNP group (n = 15). AMI model was induced by ligating the left anterior descending branch of the coronary artery, and CNP was pumped through the femoral vein starting 30 min before ischemia and continuing until 1 h after AMI. The occurrence of ventricular arrhythmias after ischemia and heart rate variability (HRV) were recorded and analyzed. The plasma norepinephrine level was detected at 15 min after AMI. Ventricular electrophysiological parameters including ventricular effective refractory period (ERP), ERP dispersion, ventricular action potential duration (APD) alternans and ventricular fibrillation threshold (VFT) were measured one hour after AMI. Then, the expressions of cyclic guanosine monophosphate in myocardial tissue and left stellate ganglion were examined. Compared to sham group, AMI significantly shortened the ERP, augmented ERP dispersion, elevated APD alternans cycle length, reduced VFT, and increased the incidence of ventricular arrhythmias. Moreover, AMI increased the sympathetic component of HRV, raised plasma norepinephrine levels, and decreased the cyclic guanosine monophosphate levels in myocardium and left stellate ganglion. All those changes were attenuated by CNP treatment. These findings suggest that CNP protected against ventricular arrhythmias in rats with AMI, potentially by inhibiting ischemia-induced cardiac sympathetic hyperactivity and cardiac electrophysiology instability.

5-HT2B, 5-HT7, and DA2 Receptors Mediate the Effects of 5-HT and DA on Agonistic Behavior of the Chinese Mitten Crab (Eriocheir sinensis).

The Chinese mitten crab (Eriocheir sinensis) is a commercially important crab in China and is usually managed at high stocking densities. Agonistic behavior directly impacts crab integrity, survival, and growth and results in economic losses. In the present study, we evaluated the modulatory effects of serotonin (5-HT) and dopamine (DA) though the 5-HT2 and DA2 receptor-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway on agonistic behavior. The results showed that injection of either 10-6 mol/crab 5-HT or DA reduced the agonistic behavior of E. sinensis (P < 0.05), as did 10-10 mol/crab DA and 10-8 mol/crab 5-HT and DA (P < 0.05); however, a dose of 10-10 mol/crab 5-HT promoted agonistic behavior. 5-HT significantly increased the mRNA expression level of 5-HT7 receptor and reduced that of the DA2 receptor in the cerebral ganglion (P < 0.05). In contrast to 5-HT, DA significantly decreased 5-HT2B mRNA levels and increased 5-HT7 and DA2 receptor levels in the thoracic ganglia (P < 0.05). In addition, injections of either 5-HT or DA increased the cAMP and PKA levels in hemolymph (P < 0.05). By using in vitro culture of the thoracic ganglia, the current study showed that ketanserin (5-HT2 antagonist) and [R(-)-TNPA] (DA2 agonist) had obvious effects on the expression levels of the two receptors (P < 0.05). In vivo experiments further demonstrated that ketanserin and [R(-)-TNPA] could both significantly reduce the agonistic behavior of the crabs (P < 0.05). Furthermore, both ketanserin and [R(-)-TNPA] promoted the cAMP and PKA levels (P < 0.05). The injection of CPT-cAMP (cAMP analogue) elevated the PKA levels and inhibited agonistic behavior. In summary, this study showed that 5HT-2B and DA2 receptors were involved in the agonistic behavior that 5-HT/DA induced through the cAMP-PKA pathway in E. sinensis.

PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge

Prevalence of prior stressful experience is linked to high incidence of chronic pain. Stress, particularly repeated stress, is known to induce maladaptive neuroplasticity along peripheral and central pain transmission pathways. These maladaptive neuroplastic events facilitate sensitization of nociceptive neurons and transition from acute to chronic pain. Pro-inflammatory and pain mediators are involved in inducing neuroplasticity. Pain mediators such as prostaglandin E2 (PGE2), EP4 receptor and transient receptor potential vanilloid-1 (TRPV1) contributes to the genesis of chronic pain. In this study, we examined role of PGE2/EP4 signaling and TRPV1 signaling in repeated restraint stress-induced prolongation of sensitization pain, a model for transition from acute to chronic pain, in both in vivo and in vitro models. We found that pre-exposure to single restraint stress induced analgesia that masked sensitization pain evoked by subsequent PGE2 challenge. However, pre-exposure to 3d consecutive restraint stress not only prolonged sensitization pain, but also increased stress hormone corticosterone (CORT) in serum, COX2 levels in paw skin, EP4 and TRPV1 levels in dorsal root ganglion (DRG) and paw skin. Pre-exposure to CORT for 3d, not 1d, also prolonged sensitization pain evoked by PGE2. Co-injection of glucocorticoid receptor (GR) antagonist RU486, COX2 inhibitor NS-398, EP4 receptor antagonist L161, 982 or TRPV1 antagonist capsazepine prevented 3d restraint stress prolonged sensitization pain evoked by PGE2. In DRG cultures, CORT increased EP4 and TRPV1 protein levels through GR activation. These data suggest that PGE2/EP4 signaling and TRPV1 signaling in peripheral pain pathway contributes to repeated stress-predisposed transition from acute to chronic pain.

Beta-nerve growth factor gene therapy alleviates pyridoxine-induced neuropathic damage by increasing doublecortin and tyrosine kinase A in the dorsal root ganglion.

Beta-nerve growth factor (β-NGF) is known to be a major leading cause of neuronal plasticity. To identify the possible action mechanisms of β-NGF gene therapy for sciatic nerve recovery, experimental dogs were randomly divided into control, pyridoxine, and pyridoxine + β-NGF groups. We observed chronological changes of morphology in the dorsal root ganglia in response to pyridoxine toxicity based on cresyl violet staining. The number of large neurons positive for cresyl violet was dramatically decreased after pyridoxine intoxication for 7 days in the dorsal root ganglia and the neuron number was gradually increased after pyridoxine withdrawal. In addition, we also investigated the effects of β-NGF gene therapy on neuronal plasticity in pyridoxine-induced neuropathic dogs. To accomplish this, tyrosine kinase receptor A (TrkA), βIII-tubulin and doublecortin (DCX) immunohistochemical staining was performed at 3 days after the last pyridoxine treatment. TrkA-immunoreactive neurons were dramatically decreased in the pyridoxine group compared to the control group, but strong TrkA immunoreactivity was observed in the small-sized dorsal root ganglia in this group. TrkA immunoreactivity in the dorsal root ganglia was similar between β-NGF and control groups. The numbers of βIII-tubulin- and DCX-immunoreactive cells decreased significantly in the pyridoxine group compared to the control group. However, the reduction of βIII-tubulin- and DCX-immunoreactive cells in the dorsal root ganglia in the β-NGF group was significantly ameliorated than that in the pyridoxine group. These results indicate that β-NGF gene therapy is a powerful treatment of pyridoxine-induced neuropathic damage by increasing the TrkA and DCX levels in the dorsal root ganglia. The experimental protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Seoul National University, South Korea (approval No. SNU-060623-1, SNU-091009-1) on June 23, 2006 and October 9, 2009, respectively.

Tonsil cancer treated with radiotherapy during a pregnancy: a case report

AbstractIntroduction:Cancer during pregnancy has an incidence of 1/1,000, and when diagnosed, the most common ones are breast cancer (1/10,000), Hodgkin’s lymphoma (1/6,000), and head and neck cancer (1/10,000). If a diagnosis is made during pregnancy, the treatment cannot wait until delivery, and there is concern about the effects that radiotherapy may have on the foetus. The multidisciplinary group has to assess and ethically make decisions with regard to the mother and foetus.Clinical case:A 35-year-old female, a carrier of Behcet’s disease, underwent 5 years of treatment with hydroxychloroquine, prednisone and low-molecular-weight heparin (the patient being a carrier of Behcet’s disease, there is a high risk for cancer of the oral cavity and oropharynx with an HR of 2·11, so the cancer could be related to the tonsil). The patient’s oncological situation started on December 2017 with a volume increase in preauricular, parotid and right mandibular angle, with a progressive growth. At this time, the foetus was of 17·5 weeks of gestation. An oral cavity tumour that invaded the right retromolar triangle was observed, and upon biopsy, a basaloid squamous cell carcinoma was diagnosed.Radiotherapy treatment was started at 22 weeks of gestation; intensity-modulated radiation therapy (IMRT) was planned with a dose of 69·96 Gy to the primary tumour and 59·4 Gy to ganglion levels II, III and IV, bilaterally in 33 fractions. At fraction 27 a significant decrease in tumour volume was noted, so adaptive radiotherapy was performed to complete the treatment. Currently the patient has no clinical evidence of tumour pathology.Discussion:The risk of radiation exposure in pregnant women (after 20 weeks of gestation), being treated for cancers of the tonsil, reaching the foetus is minimal, with a reduced risk of a few or no effects.Conclusions:Radiotherapy in tonsil cancer has been shown to be effective in combination with chemotherapy for local control of the disease. In the case of this pregnant patient, radiotherapy, as the only modality, provided local control and little exposure of radiation to the foetus.

Genomic Resolution of DLX-Orchestrated Transcriptional Circuits Driving Development of Forebrain GABAergic Neurons

SUMMARYDLX transcription factors (TFs) are master regulators of the developing vertebrate brain, driving forebrain GABAergic neuronal differentiation. Ablation of Dlx1&2 alters expression of genes that are critical for forebrain GABAergic development. We integrated epigenomic and transcriptomic analyses, complemented with in situ hybridization (ISH), and in vivo and in vitro studies of regulatory element (RE) function. This revealed the DLX-organized gene regulatory network at genomic, cellular, and spatial levels in mouse embryonic basal ganglia. DLX TFs perform dual activating and repressing functions; the consequences of their binding were determined by the sequence and genomic context of target loci. Our results reveal and, in part, explain the paradox of widespread DLX binding contrasted with a limited subset of target loci that are sensitive at the epigenomic and transcriptomic level to Dlx1&2 ablation. The regulatory properties identified here for DLX TFs suggest general mechanisms by which TFs orchestrate dynamic expression programs underlying neurodevelopment.

Effect of endomorphin-2 on orofacial pain induced by orthodontic tooth movement in rats.

Endomorphin-2 demonstrates potent antinociceptive effects in various pain models. The objectives of the present study were to explore the role of endomorphin-2 in the modulation of orofacial pain induced by orthodontic tooth movement in rats. An orthodontic pain model was established in male Sprague-Dawley rats by ligating coiled springs to mimic orthodontic force (40g). On days 0, 1, 3, 5, 7, and 14 following orthodontic tooth movement, bite force was recorded as a surrogate measure of orthodontic pain. Ipsilateral trigeminal ganglia, trigeminal nucleus caudalis, and periodontal tissues were harvested for immunostaining. Endomorphin-2, endomorphin-2+naloxone (a non-selective opioid receptor antagonist), naloxone, and saline were injected into trigeminal ganglia and periodontal tissues to explore the role of endomorphin-2 on orthodontic pain. The results showed that following orthodontic tooth movement, endomorphin-2 expression levels in trigeminal ganglia were elevated on days 1, 3, 5, and 7. Orthodontic pain levels were increased on days 1, 3, and 5. The administration of endomorphin-2 into both trigeminal ganglia and periodontal tissues alleviated orthodontic pain. Moreover, the effects of endomorphin-2 could be blocked by naloxone completely in trigeminal ganglia but only partially in periodontal tissues. Therefore, endomorphin-2 plays an important role in the modulation of orthodontic pain both centrally and peripherally, probably through different pathways.

PGE2/EP4 receptor and TRPV1 channel are involved in repeated restraint stress-induced prolongation of sensitization pain evoked by subsequent PGE2 challenge

Prevalence of prior stressful experience is linked to high incidence of chronic pain. Stress, particularly repeated stress, is known to induce maladaptive neuroplasticity along peripheral and central pain transmission pathways. These maladaptive neuroplastic events facilitate sensitization of nociceptive neurons and transition from acute to chronic pain. Pro-inflammatory and pain mediators are involved in inducing neuroplasticity. Pain mediators such as prostaglandin E2 (PGE2), EP4 receptor and transient receptor potential vanilloid-1 (TRPV1) contribute to the genesis of chronic pain. In this study, we examined the role of PGE2/EP4 signaling and TRPV1 signaling in repeated restraint stress-induced prolongation of sensitization pain, a model for transition from acute to chronic pain, in both in vivo and in vitro models. We found that pre-exposure to single restraint stress induced analgesia that masked sensitization pain evoked by subsequent PGE2 challenge. However, pre-exposure to 3d consecutive restraint stress not only prolonged sensitization pain, but also increased stress hormone corticosterone (CORT) in serum, COX2 levels in paw skin, and EP4 and TRPV1 levels in dorsal root ganglion (DRG) and paw skin. Pre-exposure to CORT for 3d, not 1d, also prolonged sensitization pain evoked by PGE2. Co-injection of glucocorticoid receptor (GR) antagonist RU486, COX2 inhibitor NS-398, EP4 receptor antagonist L161,982 or TRPV1 antagonist capsazepine prevented 3d restraint stress prolonged sensitization pain evoked by PGE2. In DRG cultures, CORT increased EP4 and TRPV1 protein levels through GR activation. These data suggest that PGE2/EP4 signaling and TRPV1 signaling in peripheral pain pathway contribute to repeated stress-predisposed transition from acute to chronic pain.

Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent.

Sensory neurones exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The present study aimed to determine the mechanisms underlying sex-dependent PRL sensitivity in sensory neurones. A quantitative reverse transcriptase-polymerase chain reaction shows that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlrcre/+ ;Rosa26LSL-tDTomato/+ reporter mice, percentages of Prlr+ sensory neurones in female and male DRG are also similar. Characterisation of Prlr+ DRG neurones using immunohistochemistry and electrophysiology revealed that Prlr+ DRG neurones are mainly peptidergic nociceptors in females and males. However, sensory neurone type-dependent expression of Prlr is sex dimorphic. Thus, Prlr+ populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr+ DRG neurones are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurones in females. Specifically, Prlr+ /IB4+ /CGRP+ neurones are four- to five-fold higher in numbers in female DRG. By contrast, Prlr+ /IB4- /CGRP+ /5HT3a+ /NPYR2- are predominant in male DRG. Prlr+ /IB4- /CGRP- , Prlr+ /IB4- /CGRP+ and Prlr+ /IB4- /CGRP+ /NPYR2+ neurones are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism by which sensory neurone type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL.

Sex differences in sympathetic gene expression and cardiac neurochemistry in Wistar Kyoto rats.

The stellate ganglia are the predominant source of sympathetic innervation to the heart. Remodeling of sympathetic nerves projecting to the heart has been observed in several cardiovascular diseases, and sympathetic dysfunction contributes to cardiac pathology. Wistar Kyoto rats are a common model for the study of cardiovascular diseases, but we lack a profile of the baseline transcriptomic and neurochemical characteristics of their cardiac sympathetic neurons. Most studies of cardiovascular disease have used male animals only, but in the future both male and female animals will be used for these types of studies; therefore, we sought to characterize the transcriptome of male and female stellate ganglia and to correlate that with catecholamine and acetylcholine content in the heart. We have generated a dataset of baseline RNA expression in male and female Wistar Kyoto rat stellate ganglia using RNA-seq, and have measured neurotransmitter levels in heart and stellate ganglia using HPLC and mass spectrometry. We identified numerous gene expression differences between male and female stellates, including genes encoding important developmental factors, receptors and neuropeptides. Female hearts had significantly higher neurotransmitter content than male hearts; however, no significant differences were detected in expression of the genes encoding neurotransmitter synthetic enzymes. Similarly, no statistically significant differences were identified between the sexes in cardiac tyrosine hydroxylase levels.

Effect of Electroacupuncture on Hyperalgesia and Vasoactive Neurotransmitters in a Rat Model of Conscious Recurrent Migraine.

Migraine onset is associated with the abnormal release of vasoactive neurotransmitters from perivascular nerves, and these neurotransmitters are involved in the pathophysiology of migraine. Hyperalgesia is a key feature of migraine, and accumulating evidence indicates that electroacupuncture (EA) at the single acupuncture point (Fengchi [GB20]) is effective in ameliorating hyperalgesia. In clinical practice, multiple acupuncture points are widely used, especially GB20 and Yanglingquan (GB34). However, the role played by vasoactive neurotransmitters in acupuncture antihyperalgesic effect at the single or multiple acupuncture points remains unknown. We aimed to determine whether EA would exert its antihyperalgesic effects by modulating vasoactive neurotransmitter release from the perivascular nerves. Furthermore, we examined whether targeting multiple acupuncture points would be more effective than targeting a single point in reducing hyperalgesia. The mechanical and thermal hyperalgesia were evaluated by measuring the facial and hind-paw mechanical withdrawal thresholds, tail-flick and hot-plate latencies. Plasma concentrations of vasoactive neurotransmitters were determined using rat-specific ELISA kits from jugular vein, including calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), pituitary adenylate cyclase-activating polypeptide (PACAP), nitric oxide (NO), and endothelin-1 (ET-1). The result suggested that EA significantly ameliorated the mechanical and thermal hyperalgesia, reduced c-Fos levels in the trigeminal ganglion, and attenuated plasma and dural levels of vasoactive neurotransmitters, especially in the multiple acupuncture points group (GB20+GB34). In conclusion, EA exerts antihyperalgesic effect in a rat model of conscious recurrent migraine, possibly via modulation of the vasoactive neurotransmitters. Furthermore, targeting multiple acupuncture points is more effective than targeting a single point in reducing hyperalgesia.

IL-10 and CXCL2 in trigeminal ganglia in neuropathic pain

Many trigeminal neuropathic pain patients suffer severe chronic pain. The neuropathic pain might be related with cross-excitation of the neighboring neurons and satellite glial cells (SGCs) in the sensory ganglia and increasing the pain signals from the peripheral tissue to the central nervous system. We induced trigeminal neuropathic pain by infraorbital nerve constriction injury (IONC) in Sprague-Dawley rats. We tested cytokine (CXCL2 and IL-10) levels in trigeminal ganglia (TGs) after trigeminal neuropathic pain induction, and the effect of direct injection of the anti-CXCL2 and recombinant IL-10 into TG. We found that IONC induced pain behavior. Additionally, IONC induced satellite glial cell activation in TG and cytokine levels of TGs were changed after IONC. CXCL2 levels increased on day 1 of neuropathic pain induction and decreased gradually, with IL-10 levels showing the opposite trend. Recombinant IL-10 or anti-CXCL2 injection into TG decreased pain behavior. Our results show that IL-10 or anti-CXCL2 are therapy options for neuropathic pain.

SLC30A10 transporter in the digestive system regulates brain manganese under basal conditions while brain SLC30A10 protects against neurotoxicity

The essential metal manganese becomes neurotoxic at elevated levels. Yet, the mechanisms by which brain manganese homeostasis is regulated are unclear. Loss-of-function mutations in SLC30A10, a cell surface-localized manganese efflux transporter in the brain and liver, induce familial manganese neurotoxicity. To elucidate the role of SLC30A10 in regulating brain manganese, we compared the phenotypes of whole-body and tissue-specific Slc30a10 knockout mice. Surprisingly, unlike whole-body knockouts, brain manganese levels were unaltered in pan-neuronal/glial Slc30a10 knockouts under basal physiological conditions. Further, although transport into bile is a major route of manganese excretion, manganese levels in the brain, blood, and liver of liver-specific Slc30a10 knockouts were only minimally elevated, suggesting that another organ compensated for loss-of-function in the liver. Additional assays revealed that SLC30A10 was also expressed in the gastrointestinal tract. In differentiated enterocytes, SLC30A10 localized to the apical/luminal domain and transported intracellular manganese to the lumen. Importantly, endoderm-specific knockouts, lacking SLC30A10 in the liver and gastrointestinal tract, had markedly elevated manganese levels in the brain, blood, and liver. Thus, under basal physiological conditions, brain manganese is regulated by activity of SLC30A10 in the liver and gastrointestinal tract, and not the brain or just the liver. Notably, however, brain manganese levels of endoderm-specific knockouts were lower than whole-body knockouts, and only whole-body knockouts exhibited manganese-induced neurobehavioral defects. Moreover, after elevated exposure, pan-neuronal/glial knockouts had higher manganese levels in the basal ganglia and thalamus than controls. Therefore, when manganese levels increase, activity of SLC30A10 in the brain protects against neurotoxicity.

Evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammation and maintaining mitochondrial anti-oxidant functions.

Chemotherapy-induced neuropathic pain (CINP) is a common and debilitating side effect of cancer treatment. Evodiamine, a major effective compound isolated from Evodia rutaecarpa, has been associated with anti-inflammatory and anti-nociceptive effects, an important therapeutic strategy for the treatment of neuropathic pain. However, the effects of evodiamine on CINP remain unknown. Thus, this study aims to investigate the pharmacological potential of evodiamine in attenuating paclitaxel-induced peripheral neuropathy. The results showed that evodiamine enhanced but not reduced the sensitivity of cancer cells to paclitaxel treatment. In a rat model of paclitaxel-induced peripheral neuropathy, evodiamine significantly ameliorated the development of mechanical and thermal hypersensitivity. Moreover, paclitaxel-induced the loss of intraepidermal nerve fibers was markedly inhibited by evodiamine administration. This inhibitory effect was accompanied with the decrease in inflammatory and chemoattractant cytokines level in dorsal root ganglia (DRG), such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α and monocyte chemoattractant protein-1. In addition, evodiamine administration limited paclitaxel-induced elevation of oxidative stress in DRG tissues. The mitochondrial dysfunction evoked by paclitaxel was also remarkably improved in evodiamine-treated rats, evidenced by restoration of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), uncoupling protein 2 (UCP2), and superoxide dismutase 2 (SOD2) expression. In in vitro studies, we found that evodiamine prevented paclitaxel-induced the loss of mitochondrial membrane potential and PGC-1α, UCP2 and SOD2 expression in DRG cells. In conclusion, our study demonstrates that evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammatory response and maintaining mitochondrial anti-oxidant functions, indicating that evodiamine may be a promising therapeutic agent for CINP treatment.